PROJECT SUMMARY The objective of my laboratory is to characterize how molecular communication between nutritional constituents and innate immune cells lead to diet-dependent altered inflammation and disease outcomes. To accomplish this goal, we have developed a mouse model of dietary manipulation and lipopolysaccharide (LPS)-induced acute inflammation (endotoxemia). This system of acute inflammation is advantageous because we can dissect the relationship between diet and immunity without the confounding factors of an active infection or chronic disease. Using our mouse model, our initial efforts have begun to elucidate the role of Western Diet (WD) in driving chronic systemic inflammation, altered neutrophil and monocyte cell migration and function, and increased severity and mortality in an LPS-driven acute inflammatory shock model (endotoxemia). The WD is a diet high in fat and sucrose and low in fiber, and is the most prevalent diet in Westernized countries (1). The impact of the WD diet on microbiome-associated inflammation has been extensively studied (10-16); however, the molecular mechanisms of WD-associated fatty acids in regulation of inflammation and WD-dependent regulation of the innate immune response to microbial products remain fragmented and poorly characterized. Our goal for the next 5 years is to understand the molecular mechanism by which WD directly regulates immunity and disease kinetics. To accomplish this goal, we will combine multifactorial studies to address undefined paradigms within our field, including: Project 1) Defining the impact of WD-associated fatty acids on monocyte LPS-tolerance and endotoxemia outcome, Project 2) Identifying alternatively regulated pathways in WD-dependent aged neutrophils and elucidate the impact of this cell population on disease outcomes, and Project 3) Elucidating the temporal control and plasticity of immunological reprogramming by WD. This research program focuses on determining the effects of WD on systemic inflammation, cell function, and disease kinetics. A mechanistic understanding of these processes are necessary to develop efficacious dietary strategies to reduce metabolic inflammation and dietary interventions that improve disease outcomes associated with a WD-fed population.